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Breast Cancer Research and Treatment Jul 2024Although changes in circulating tumour DNA (ctDNA) in breast cancer are well described, the kinetics of their fluctuations has not been described over short timescales....
PURPOSE
Although changes in circulating tumour DNA (ctDNA) in breast cancer are well described, the kinetics of their fluctuations has not been described over short timescales. We investigated ctDNA dynamics during alternating cycles of chemotherapy and hormonal treatment in pre-treated patients with oestrogen receptor-positive metastatic breast cancer.
METHODS
Patients received alternating, 9-week cycles of eribulin and aromatase inhibitors (AIs). The clinical primary endpoint, progression-free survival (PFS), was monitored at 3, 6 and 9 months; secondary endpoints, clinical benefit rate (CBR), safety and tolerability profiles, were also assessed. Importantly, ctDNA fluctuations were monitored using the Oncomine™ Breast cfDNA assay to test whether biomarkers may change rapidly between chemotherapy and aromatase inhibitor (AI) treatment in the setting of advanced breast cancer, potentially reflecting disease dynamics.
RESULTS
The median PFS was 202 days (95% CI: 135-undefined) and 235 days (95% CI: 235-undefined) at 6 and 9 months, respectively, with a 50% CBR at both 6 and 9 months. Dynamic changes in ctDNA were observed in short timescales between chemotherapy and AI treatment and support the clinical benefit (CB) seen in individual patients and, critically, appear informative of acquired resistance in real time.
CONCLUSION
Changes in ctDNA can occur rapidly and reflect changes in patients' clinical tumour responses (NCT02681523).
Topics: Adult; Aged; Female; Humans; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Biomarkers, Tumor; Breast Neoplasms; Circulating Tumor DNA; Furans; Ketones; Neoplasm Metastasis; Polyether Polyketides; Treatment Outcome
PubMed: 38581534
DOI: 10.1007/s10549-024-07316-8 -
Cancer Reports (Hoboken, N.J.) Apr 2024Anastrozole is a selective aromatase inhibitor used for the treatment of postmenopausal hormone-sensitive breast cancer. The major side effects include osteoporosis,...
Drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method following mild COVID-19 in a patient under anastrozole therapy-A case report.
BACKGROUND
Anastrozole is a selective aromatase inhibitor used for the treatment of postmenopausal hormone-sensitive breast cancer. The major side effects include osteoporosis, hypercholesterolemia, and musculoskeletal events, such as arthralgia and myalgia. Other adverse events are rare, including symptoms of acne, masculinization, and drug-induced liver injury, with the latter reported in a few cases only.
CASE
Here, we report on a patient under anastrozole therapy who developed drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method 5 weeks after a mild SARS-CoV-2 infection, which is, to the best of our knowledge, the first report of its kind involving anastrozole. Discontinuation of anastrozole resulted in a marked improvement of the alanine aminotransaminase, and aspartate aminotransaminase as well as normalized lactate dehydrogenase serum levels already seen after 26 days. Surprisingly, however, the cholestatic serum markers gamma-glutamyl transpeptidase and alkaline phosphatase showed a further rise, and took another 4 weeks to drop significantly.
CONCLUSION
The presentation of this case is meant to alert physicians to a potential drug-induced liver injury following mild SARS-CoV-2 infection in patients under anastrozole medication.
Topics: Humans; Anastrozole; COVID-19; SARS-CoV-2; Chemical and Drug Induced Liver Injury; Aromatase Inhibitors
PubMed: 38577842
DOI: 10.1002/cnr2.2028 -
Bone Reports Jun 2024Hormone therapy following surgery reduces the risk of breast cancer (BC) recurrence and progression of hormone-sensitive BC, especially in postmenopausal women. Despite... (Review)
Review
Hormone therapy following surgery reduces the risk of breast cancer (BC) recurrence and progression of hormone-sensitive BC, especially in postmenopausal women. Despite the antitumor efficacy of hormone therapy, particularly of aromatase inhibitors, they cause long-term side effects, mainly bone density reduction. Exercise can slow the rate of bone loss, which reduces the risk of fractures from osteoporosis, and could be an integrative treatment able to mitigate the BC treatment side effects positively impacting bone health. This narrative review aims to discuss studies on the effect of exercise on bone health in BC women undergoing aromatase inhibitors, highlighting the possible role of exercise as complementary to conventional therapies. Additionally, according to the literature revision, exercise practical applications to improve bone health in these patients are summarized.
PubMed: 38577250
DOI: 10.1016/j.bonr.2024.101756 -
Frontiers in Endocrinology 2024Estrogen receptor positive (ER) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this... (Review)
Review
Estrogen receptor positive (ER) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and "reversible" senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and "reversible" senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER breast cancer.
Topics: Animals; Female; Humans; Breast Neoplasms; Estrogen Receptor Modulators; Drug Resistance, Neoplasm; Neoplasm Recurrence, Local; Receptors, Estrogen; Autophagy
PubMed: 38567308
DOI: 10.3389/fendo.2024.1298423 -
BioRxiv : the Preprint Server For... Mar 2024Resistance to endocrine therapy is a major challenge of managing estrogen receptor positive (ER+) breast cancer. We previously reported frequent overexpression of FGFR4...
BACKGROUND
Resistance to endocrine therapy is a major challenge of managing estrogen receptor positive (ER+) breast cancer. We previously reported frequent overexpression of FGFR4 in endocrine resistant cell lines and breast cancers that recurred and metastasized following endocrine therapy, suggesting FGFR4 as a potential driver of endocrine resistance. In this study, we investigated the role of FGFR4 in mediating endocrine resistance and explored the therapeutic potential of targeting FGFR4 in advanced breast cancer.
METHODS
A gene expression signature of FGFR4 activity was examined in ER+ breast cancer pre- and post-neoadjuvant endocrine therapy and the association between FGFR4 expression and patient survival was examined. A correlation analysis was used to uncover potential regulators of FGFR4 overexpression. To investigate if FGFR4 is necessary to drive endocrine resistance, we tested response to FGFR4 inhibition in long term estrogen deprived (LTED) cells and their paired parental cells. Doxycycline inducible FGFR4 overexpression and knockdown cell models were generated to examine if FGFR4 was sufficient to confer endocrine resistance. Finally, we examined response to FGFR4 monotherapy or combination therapy with fulvestrant in breast cancer cell lines to explore the potential of FGFR4 targeted therapy for advanced breast cancer and assessed the importance of PAM50 subtype in response to FGFR4 inhibition.
RESULTS
A FGFR4 activity gene signature was significantly upregulated post neoadjuvant aromatase inhibitor treatment, and high FGFR4 expression predicted poorer survival in patients with ER+ breast cancer. Gene expression association analysis using TCGA, METABRIC and SCAN-B datasets uncovered ER as the most significant gene negatively correlated with FGFR4 expression. ER negatively regulates FGFR4 expression at both the mRNA and protein level across multiple ER+ breast cancer cell lines. Despite robust overexpression of FGFR4, LTED cells did not show enhanced responses to FGFR4 inhibition compared to parental cells. Similarly, FGFR4 overexpression, knockdown or hotspot mutations did not significantly alter response to endocrine treatment in ER+ cell lines, nor did FGFR4 and fulvestrant combination treatment show synergistic effects. The HER2-like subtype of breast cancer showed elevated expression of FGFR4 and an increased response to FGFR4 inhibition relative to other breast cancer subtypes.
CONCLUSIONS
Despite ER-mediated upregulation of FGFR4 post endocrine therapy, our study does not support a general role of FGFR4 in mediating endocrine resistance in ER+ breast cancer. Our data suggests that specific genomic backgrounds such as HER2 expression may be required for FGFR4 function in breast cancer and should be further explored.
PubMed: 38562741
DOI: 10.1101/2024.03.18.585626 -
Breast Cancer Research and Treatment Jul 2024We aimed to provide long-term bone mineral density (BMD) data on early breast cancer patients of the BREX (Breast Cancer and Exercise) study. The effects of exercise and... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
We aimed to provide long-term bone mineral density (BMD) data on early breast cancer patients of the BREX (Breast Cancer and Exercise) study. The effects of exercise and adjuvant endocrine treatment 10 years after randomization were analyzed, with special emphasis on aromatase inhibitor (AI) therapy discontinuation at 5 years.
METHODS
The BREX study randomized 573 pre- and postmenopausal breast cancer patients into a 1-year supervised exercise program or a control group. 372 patients were included into the current follow-up analysis. BMD (g/cm) was measured by dual-energy X-ray absorptiometry at lumbar spine (LS), left femoral neck (FN), and the total hip. Separate groups were displayed according to baseline menopausal status, and whether the patient had discontinued AI therapy at 5 years or not.
RESULTS
The BMD change from 5 to 10 years did not significantly differ between the two randomized arms. AI discontinuation at 5 years had statistically significant BMD effects. The FN BMD continued to decrease in patients who discontinued AI therapy during the first 5-year off-treatment, but the decrease was three-fold less than in patients without AI withdrawal (- 1.4% v. - 3.8%). The LS BMD increased (+ 2.6%) in patients with AI withdrawal during the first 5 years following treatment discontinuation, while a BMD decrease (-1.3%) was seen in patients without AI withdrawal.
CONCLUSION
This study is to our knowledge the first to quantify the long-term impact of AI withdrawal on BMD. Bone loss associated with AI therapy seems partially reversible after stopping treatment.
TRIAL REGISTRATION
http://www.
CLINICALTRIALS
gov/ (Identifier Number NCT00639210).
Topics: Humans; Female; Bone Density; Breast Neoplasms; Aromatase Inhibitors; Middle Aged; Follow-Up Studies; Adult; Aged; Absorptiometry, Photon; Postmenopause
PubMed: 38561578
DOI: 10.1007/s10549-024-07252-7 -
Neurobiology of Disease Jun 2024Obesity and neurometabolic diseases have been linked to neurodegenerative diseases. Our hypothesis is that the endogenous estrogenic component of human astrocytes plays...
Obesity and neurometabolic diseases have been linked to neurodegenerative diseases. Our hypothesis is that the endogenous estrogenic component of human astrocytes plays a critical role in cell response during lipotoxic damage, given that obesity can disrupt hormonal homeostasis and cause brain inflammation. Our findings showed that high concentrations of palmitic acid (PA) significantly reduced cell viability more in male astrocytes, indicating sex-specific vulnerabilities. PA induced a greater increase in cytosolic reactive oxygen species (ROS) production in males, while female astrocytes exhibited higher superoxide ion levels in mitochondria. In addition, female astrocytes treated with PA showed increased expression of antioxidant proteins, including catalase, Gpx-1 and Nrf2 suggesting a stronger cellular defence mechanism. Interestingly, there was a difference in the expression of estrogenic components, such as estrogen, androgens, and progesterone receptors, as well as aromatase and 5α-reductase enzymes, between males and females. PA induced their expression mainly in females, indicating a potential protective mechanism mediated by endogenous hormones. In summary, our findings highlight the impact of sex on the response of human astrocytes to lipotoxicity. Male astrocytes appear to be more susceptible to cellular damage when exposed to high concentrations of fatty acids.
Topics: Humans; Astrocytes; Palmitic Acid; Female; Male; Reactive Oxygen Species; Sex Characteristics; Cell Survival; Cells, Cultured; NF-E2-Related Factor 2; Glutathione Peroxidase; Catalase; Aromatase; Oxidative Stress; Mitochondria; Glutathione Peroxidase GPX1
PubMed: 38552721
DOI: 10.1016/j.nbd.2024.106489 -
Biomedicine & Pharmacotherapy =... May 2024Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The aim of this study was to investigate the therapeutic potential of vitamin C,...
Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The aim of this study was to investigate the therapeutic potential of vitamin C, glutamine, mesalazine, hydralazine, and alendronate as new drug candidates for the treatment of letrozole-induced PCOS in female Wistar rats. PCOS was induced in rats by intramuscular injection of estradiol valerate (2 mg/kg body weight for 28 days). The rats then received normal saline (PCOS group), letrozole (0.5 mg/kg), vitamin C (100 mg/kg), glutamine (1000 mg/kg), mesalazine (200 mg/kg), hydralazine (30 mg/kg), and alendronate (17.5 mg/kg). Serum testosterone, LH, FSH, estradiol and progesterone levels were determined by ELISA method. H&E staining was used for histological analysis in the ovarian tissues. The groups treated with hydralazine and alendronate, show a significant decrease in testosterone, LH hormone, cystic and atretic follicles, and a significant increase in the number of single layer, multilayer, antral, graafian follicles and the volume of corpus luteum as compared to the PCOS group. Hydrolazine and alendronate appear to be effective in restoring folliculogenesis and increasing ovulation in PCOS rat. So that the natural process of ovulation and the improvement of the histology of polycystic ovaries and its shift towards healthy and active ovaries were observed. This finding supports the potential beneficial effect of hydrolazine and alendronate on improving PCOS complication.
Topics: Animals; Female; Rats; Alendronate; Aromatase Inhibitors; Disease Models, Animal; Estradiol; Hydralazine; Letrozole; Luteinizing Hormone; Ovary; Polycystic Ovary Syndrome; Rats, Wistar; Testosterone
PubMed: 38552442
DOI: 10.1016/j.biopha.2024.116504 -
Scientific Reports Mar 2024Genitourinary syndrome of menopause (GSM) is the leading cause of vaginal symptoms in breast cancer survivors treated with aromatase inhibitors. However, there are...
Genitourinary syndrome of menopause (GSM) is the leading cause of vaginal symptoms in breast cancer survivors treated with aromatase inhibitors. However, there are currently no effective treatment options available for women with a history of breast cancer. Recent research has established that changes in the vaginal microbiome may be linked to GSM. Most studies have assessed the microbiome without accounting for the estrogen status. It remains unknown whether the vaginal microbiome differ among patients with a low estrogenic state with and without vulvovaginal symptoms. To address such research questions, our study compares the vaginal microbiomes among breast cancer survivors treated with aromatase inhibitors with and without vulvovaginal symptoms. A total of 50 breast cancer survivors treated with aromatase inhibitors were recruited, among whom 25 had vulvovaginal symptoms and 25 had no vulvovaginal symptoms. Vaginal swabs were collected. DNA extraction, followed by sequencing of the V3-V4 regions of the 16S ribosomal RNA gene, were performed. Differential abundance analysis was conducted by linear discriminant analysis effect size. Taxonomy assignment, alpha diversity and beta diversity were examined. The relative abundance of genus Sneathia and genus Gardnerella was significantly increased in vulvovaginal symptoms group with no differences in bacterial diversity and richness.
Topics: Female; Humans; Breast Neoplasms; Cancer Survivors; Aromatase Inhibitors; Breast; Vagina; Microbiota; Menopause
PubMed: 38548910
DOI: 10.1038/s41598-024-58118-3 -
Asian Pacific Journal of Cancer... Mar 2024Gastric cancer (GC) is one of the most common malignancies and ranks third in terms of cancer-related mortality. This study aims to identify the hub genes and potential...
OBJECTIVE
Gastric cancer (GC) is one of the most common malignancies and ranks third in terms of cancer-related mortality. This study aims to identify the hub genes and potential mechanisms in GC using a bioinformatics approach.
METHODS
Microarray data GSE54129, GSE79973, GSE55696 were extracted from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) was identified using Benjamini-Hochberg method in the limma package. GO and KEGG pathway enrichment analyses of the DEGs were conducted. Furthermore, protein-protein interaction network was constructed the STRING platform, and the hub genes were discovered using Maximal Clique Centrality method via cytoHubba. The predictive significance of hub genes was evaluated through GSE15459 dataset.
RESULTS
A total of 73 genes was identified as DEGs in GC. Volcano plots and heatmaps of DEGs were visualized. Functional enrichment analysis revealed that the genes were mostly enriched in response to xenobiotic stimulus, digestion, cellular hormone metabolic process, extracellular matrix structural constituent, calcium-dependent cysteine-type endopeptidase activity, aromatase activity, apical part of cell, basal part of cell, and apical plasma membrane. Regarding KEGG pathway-enrichment, the genes were mainly involved in Drug metabolism-cytochrome P450, Retinol metabolism, Chemical carcinogenesis-DNA adducts, Gastric acid secretion, and Metabolism of xenobiotics by cytochrome P450. By combining the results of Cytohubba, the top five intersecting genes identified were SPP1, INHBA, MMP7, THBS2 and FAP. Kapplan-Meier analysis results showed that these 5 hub genes were highly related to the overall survival of patients.
CONCLUSION
SPP1, INHBA, MMP7, THBS2, and FAP were identified as prospective biomarkers and therapeutic targets for GC that might be utilized for prognostic evaluation and scheme selection.
Topics: Humans; Transcriptome; Stomach Neoplasms; Matrix Metalloproteinase 7; Biomarkers, Tumor; Gene Expression Profiling; Computational Biology; Cytochrome P-450 Enzyme System
PubMed: 38546071
DOI: 10.31557/APJCP.2024.25.3.885